Altered Expression of Insulin Receptor Isoforms in Breast Cancer

Purpose: Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. Experimental Design: mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A: IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. Results: The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A: IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A: IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. Conclusions: The reduction in IR-B expression is the key to the altered IR-A: IR-B ratio observed in breast cancer. The IR-A: IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.